Respiratory Syncytial Virus Immunopathology and Vaccine Development


The antigenic differences that occur among these viruses might contribute to the ability of RSV to establish reinfections throughout life.9


Respiratory Syncytial Virus Immune Response Innate Immunity


Innate immunity is the first line of defense against infectious disease. RSV infection triggers innate immune responses, which encompass the main defense for activating and producing virus-specific adaptive immune responses. A group of proteins known as Toll-like receptors (TLRs) mediate innate immunity responses and lead to secretion of inflammatory cytokines. Recently, the F glycoprotein of RSV was shown to activate TLR4 in the context of additional interactions with the CD14 receptor, primarily expressed on monocytes. The TLR4—CD14 complex leads to activation of nuclear factor (NF)-κB, and the production of proinflammatory and pleiotropic cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and IL-10. Although these cytokines have been shown to be important in clearing the virus, they might also contribute to patholology when secreted in excess.10


In vitro


studies performed on epithelial cells have shown that RSV infection also promotes the secretion of cytokines and chemokines, such as IL-8 (CXCL8), regulated on activation normal T cell-expressed and secreted (RANTES; CCL5), CCL4 and eotaxin-1 (CCL11).11


These activate and


recruit neutrophils, monocytes, memory T cells and eosinophils into infected tissue. The immune cells secrete not only additional pro-inflammatory cytokines, such as TNF, IL-6 and IL-8, but also inhibitory cytokines.12


clearance. Studies of RSV-specific immune responses in mice have shown that, although both CD4+ and CD8+ memory T cells contribute to protection against RSV, they might also induce immunopathology.18


The


memory CD4+ T cell response to RSV includes T helper 1 (Th1) and 2 (Th2) cells. These cells are characterized by the cytokines that they secrete—Th1 cytokines include interleukin-2 (IL-2), TNF-α, and IFN-g, and the Th2 cytokines are represented by IL-4, IL-5, IL-10, IL-9 and IL-13.19,20


associated with reduced disease during RSV infection.21,22


Th1 and Th2 CD4+ T lymphocytes have important roles in immune regulation and function and, to some extent, are self stimulatory and reciprocally inhibitory.15


Th1 responses are generally By contrast,


These cytokines, particularly IL-9, can also be detected in bronchial secretions of infants with severe RSV bronchiolitis.24


Th2 responses, particularly those represented by IL-13 and IL-9, were shown to contribute to the severity of the disease in animal models by generating eosinophilia, goblet cell hyperplasia and mucus overproduction.15,23


Furthermore, genetic-association studies have revealed that variations in the genes encoding TH2 cytokines increase susceptibility to RSV disease.25


CD8+ Th1 cells that secrete perforin and TNF-α have a key role in viral clearance, and deficiencies in either can lead to a delay in the elimination of infected cells.14


Natural killer (NK) cells are another major


component of the innate immune system and, as a result of their cytotoxic ability, have a key role in the clearance of virus-infected cells. Chemokines, such as macrophage inflammatory protein (MIP)-1α, are important for the recruitment of NK cells to the site of infection and inflammation. Studies suggest that the secretion of chemokines by airway epithelial cells and infiltrating immune cells can cause harm by promoting immunopathology and tissue damage, with a negligible impact on viral clearance.11


Adaptive Immunity


Adaptive immunity against RSV is mediated by humoral and cellular immune responses.13


Secretory immunoglobulin Infection with RSV results in production


of neutralizing antibodies that are subgroup specific or cross-reactive. Neutralizing antibodies have an important role in protecting against RSV infection of the respiratory tract.14


(Ig)A-neutralizing antibodies are important in protecting the upper respiratory tract, whereas serum IgG antibodies are more efficient in providing protection in the lower respiratory tract.15


The IgA response is


short lived following primary infection, but can increase upon reinfection. In RSV-naïve infants, high maternal serum antibody titers are associated with less severe RSV disease. Antibodies against the F and G proteins are likely to be the most important and can provide considerable protection against severe disease, as demonstrated by that conferred by palivizumab against RSV.16


RSV does not induce


sterilizing immunological memory and infection recurs throughout life with antigenically similar strains.17


T-cell-mediated Immune Response


Although antibody responses are required for protection against RSV infection, T-cell-mediated cellular responses have a greater role in viral


US RESPIRATORY DISEASE


Recently, CD4+ IL-17-producing T cells have been classified as a new effector T cell subset, called Th17. These cells have an important role in the pathogenesis of inflammatory disorders of the gastrointestinal tract and other autoimmune diseases. Little is known about their role in viral infections, including RSV. Murine models of RSV infection showed increased expression of IL-17 in the respiratory tract.27


Th17 might have


a role in inhibiting virus-induced cell apoptosis, resulting in enhanced viral replication and persistence.28


Past Experience—Formalin-inactivated Respiratory Syncytial Virus Vaccine


The importance of the immune system in RSV pathogenesis was emphasized by the formalin-inactivated (FI)-RSV vaccine (Lot 100) trial held during 1966–1967 in children aged between two months and nine years of age.5,34


RSV vaccine recipients were exposed to RSV during the winter season, and those children who were seronegative for RSV before vaccination experienced a significant increase in the frequency and severity of RSV lower respiratory tract disease, as well as increased hospitalization. Catastrophically, two vaccinated children died of severe RSV infection. Autopsy showed severe inflammatory infiltrate suggesting an immunopathologic disease.5,29


Subsequent studies in mice showed that FI-RSV administration leads to a strong Th2 response after inoculation with wild-type RSV and a lack of a cytotoxic CD8+ Th1 response. The Th2 response augments the degree of local eosinophilia and inflammation, and suppresses CD8+ cytotoxic T-cell activation and function. In addition, recent data suggest that the FI process also resulted in the destruction of CD8+ T cell epitopes, further contributing to the low CD8+ response of vaccinees.30 As a result, RSV clearance was delayed, and viral spread and


61


In addition, CD8+ T cells present early in


infected lungs were noted to suppress the development of Th2 responses, thus limiting the development of pulmonary eosinophilia.26


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